Field of the Invention
This disclosure relates to novel B7-H3 antibodies, compositions comprising the same, and methods for using the same for detecting B7-H3 in tissues, including tumors. Also provided herein are isolated peptides and fusion proteins containing immunogenic determinants for said B7-H3 antibodies.
Description of Related Art
The following description is provided to assist the understanding of the reader. None of the information provided or references cited is admitted to be prior art.
B7-H3 is a type I transmembrane protein that shares 20%-27% amino acid identity with other B7 family members. While murine B7-H3 consists of a single extracellular variable-type immunoglobulin (Ig)V-IgC domain and a signature intracellular domain (2Ig B7-H3), human B7-H3 possesses an additional isoform, the so-called 4Ig B7-H3 that contains a nearly exact tandem duplication of the IgV-IgC domain. The 4Ig transcript is the dominant form in human tissues.
So far, only one potential receptor of murine B7-H3 called triggering receptor expressed on myeloid cells (TREM-) like transcript 2 (TLT-2) has been identified. TLT-2 belongs to the TREM receptor family, which function as modulators of cellular responses and play important roles in both innate and adaptive immunities. TLT-2 protein expression has been shown on CD8+ T-cells constitutively and is induced on activated CD4+ T-cells.
As an accessory costimulatory molecule, B7-H3 protein is not constitutively expressed on T-cells, natural killer (NK) cells, and APCs, but its expression can be induced on these cell types. B7-H3 protein is also found on osteoblasts, fibroblasts, fibroblast-like synoviocytes, and epithelial cells as well as in human liver, lung, bladder, testis, prostate, breast, placenta, and lymphoid organs. This broad expression pattern suggests more diverse immunological and probably nonimmunological functions of B7-H3, especially in peripheral tissues.
B7-H3 expression has also been found in a variety of different human cancers, including prostate cancer, clear cell renal cell carcinoma (ccRCC), non-small-cell lung cancer (NSCLC), pancreatic cancer, gastric cancer, ovarian cancer, colorectal cancer (CRC) and urothelial cell carcinoma. In prostate cancer, the intensity of expression of B7-H3 positively correlates with clinicopathological malignancy such as tumor volume, extraprostatic invasion, or Gleason score, and also correlates with cancer progression. Further, in ovarian cancer, the expression of B7-H3 correlates with lymph node metastasis and pathological progression. Thus, measuring the amount of B7-H3 protein in biological samples may aid in the early detection of cancer pathologies and may help assess the efficacy and durability of investigational drugs that inhibit the binding of the B7-H3 protein.
However, the use of B7-H3 protein expression as an accurate predictor for cancer and/or the efficacy of B7-H3 targeted therapies remains challenging. Many commercially available antibodies directed to B7-H3, such as M3.2D7, fail to specifically bind to B7-H3-Ig protein, thereby making them unreliable diagnostic reagents. See Yan et. al., Hybridoma 31(4): 267-271 (2012).